Effects of Chronic Ethanol Exposure on Lateral Orbitofrontal Cortex and Basolateral Amygdala Circuitry Abstract One of the hallmark characteristics of alcoholism is the inability to abstain from alcohol consumption despite the emergence of substantial negative interpersonal, medical and legal consequences that result from excessive drinking. Results from human neuroimaging studies and rodent models of aversion-resistant drinking, suggests that this behavioral phenotype may result from dysfunctional communication between the lateral orbitofrontal cortex (lOFC) and the basolateral amygdala (BLA). The lOFC and BLA are important for establishing stimulus/reward relationships and modifying the representation of these relationships when expected and actual outcomes diverge. Furthermore, these brain regions are known to undergo multiple forms of neuroplasticity in response to repetitive bouts of alcohol intoxication. Therefore, it is likely that alcohol induced adaptations in lOFC/BLA circuitry contribute to the behavioral deficits associated with habitual drinking after the previously rewarding effects of alcohol are replaced with negative consequences. However, it remains unclear how the lOFC and BLA communicate in-vivo to process information related to changes in stimulus/outcome relationships and how alcohol modifies this communication at lOFC/BLA synapses. Accordingly, the major goals of this application are to address these uncertainties using cutting edge in-vivo and in-vitro techniques. Aim 1 will use in-vivo fiber photometry to measure lOFC/BLA circuit activity during operant alcohol self-administration using a reward devaluation protocol to compare neural activity in ethanol- dependent and non-dependent mice in response to a change in stimulus/outcome relationships. Furthermore, Aim 2 will use in-vitro electrophysiological and optogenetic approaches to examine alcohol-related adaptations in lOFC/BLA synapses, and superresolution microscopy to evaluate changes in the density and morphology of the dendritic spines on lOFC/BLA neurons. In total, these studies will comprehensively examine the effects of chronic alcohol exposure on lOFC/BLA circuitry from the in-vivo measurement of lOFC/BLA circuit activity during an ethologically relevant behavior to the examination of functional and anatomical modifications directly at lOFC/BLA synapses. Additionally, these studies will advance the alcohol research field by providing an important foundation for the use of in-vivo fiber photometry during operant alcohol self-administration in mice. Furthermore, the skills that I will attain through the completion of these aims will greatly expand my technical abilities while training in project management, data analysis and manuscript preparation will advance my career objective of becoming an independent academic neuroscientist.